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Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):1062-1073
Cell Therapy & Immunotherapy
Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways
Kaya Xu,1,2 Jea-Young Lee,1 Yuji Kaneko,1 Julian P. Tuazon,1 Fernando Vale,1 Harry van Loveren1 and Cesario V. Borlongan1
1Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA and 2Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, China
ABSTRACT
Despite mounting evidence of a massive peripheral inflammatory response accompanying stroke, the ability of intracerebrally trans- planted cells to migrate to the periphery and sequester systemic inflammation remains unexamined. Here, we tested the hypothesis that human bone marrow mesenchymal stromal cells intracerebrally trans- planted in the brain of adult rats subjected to experimental stroke can migrate to the spleen, a vital organ that confers peripheral inflammation after stroke. Sham or experimental stroke was induced in adult Sprague- Dawley rats by a 1 hour middle cerebral artery occlusion model. One hour after surgery, rats were intracerebrally injected with human bone marrow mesenchymal stromal cells (3×105/9 mL), then euthanized on day 1, 3, or 7 for immunohistochemical assays. Cell migration assays were performed for human bone marrow mesenchymal stromal cells using Boyden chambers with the bottom plate consisting of microglia, lym- phatic endothelial cells, or both, and treated with different doses of tumor necrosis factor-a. Plates were processed in a fluorescence reader at differ- ent time points. Immunofluorescence microscopy on different days after the stroke revealed that stem cells engrafted in the stroke brain but, inter- estingly, homed to the spleen via lymphatic vessels, and were propelled by inflammatory signals. Experiments using human bone marrow mes- enchymal stromal cells co-cultured with lymphatic endothelial cells or microglia, and treated with tumor necrosis factor-a, further indicated the key roles of the lymphatic system and inflammation in directing stem cell migration. This study is the first to demonstrate brain-to-periphery migration of stem cells, advancing the novel concept of harnessing the lymphatic system in mobilizing stem cells to sequester peripheral inflam- mation as a brain repair strategy.
Introduction
Ischemic stroke continues to stand as a leading cause of death and disability worldwide, with an ongoing need for effective therapies.1 Cell-based therapies have emerged as a promising modality for stroke treatment, yet a complete under- standing of their mechanisms remains elusive.2-4 The study of stem cell therapy for stroke has focused primarily on the effects of the grafted cells within the local brain tissue, despite the recognition of a peripheral inflammatory response exacerbating the pathological outcomes in the stroke brain.5,6 Following stroke, a compromised blood-brain barrier (BBB) allows peripheral major histocompatibility complex class II (MHC-II)-positive immune cells – including neutrophils, T cells, and mono- cytes/macrophages7 – to infiltrate the brain parenchyma, perpetuating a state of cerebral inflammation.8-10 Pharmacological and cell-based anti-inflammatory meth- ods which attenuate cerebral and systemic inflammation have been shown to improve stroke outcomes.11,12 Thus, an understanding of how stem cells sequester and modulate peripheral inflammation is key for furthering the application of stem
Correspondence:
CESARIO V. BORLONGAN
cborlong@health.usf.edu
Received: September 11, 2018. Accepted: November 30, 2018. Pre-published: December 4, 2018.
doi:10.3324/haematol.2018.206581
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/1062
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